A Non-canonical Pathway from Cochlea to Brain Signals Tissue-Damaging Noise

Flores, Emma N.; Duggan, Anne; Madathany, Thomas; Hogan, Ann; Márquez, Freddie; Kumar, Gagan; Seal, Rebecca P.; Edwards, Robert H.; Liberman, M. Charles; Garcı́a-Añoveros, Jaime

doi:10.1016/j.cub.2015.01.009

Cited by 124 publications

(121 citation statements)

References 39 publications

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“…Even though three isoforms of glutamate transporters exist, Vglut3 was targeted because of its role in hearing and pain (Akil et al, 2012; Flores et al, 2015; Ruel et al, 2008; Seal et al, 2009). Here, immunofluorescence was performed to determine whether or not Vglut3 positive neurons would also be Gabrg3 positive.…”

Section: Resultsmentioning

confidence: 99%

“…Despite the loss of auditory input, noise-induced hearing loss leads to a significant increase in spontaneous activity in the CN. These electrophysiological and neuroanatomical changes have been linked to tinnitus as well as hyperacusis and ear pain (Bauer et al, 2007a; Dong et al, 2009; Flores et al, 2015; Hickox and Liberman, 2014; Kaltenbach et al, 2000). The biological mechanisms that give rise to spontaneous hyperactivity and these perceptual disturbances remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Manohar

Dahar

Adler

et al. 2016

Molecular and Cellular Neuroscience

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Severe noise-induced damage to the inner ear leads to auditory nerve fiber degeneration thereby reducing the neural input to the cochlear nucleus (CN). Paradoxically, this leads to a significant increase in spontaneous activity in the CN which has been linked to tinnitus, hyperacusis and ear pain. The biological mechanisms that lead to an increased spontaneous activity are largely unknown, but could arise from changes in glutamatergic or GABAergic neurotransmission or neuroinflammation. To test this hypothesis, we unilaterally exposed rats for 2 h to a 126 dB SPL narrow band noise centered at 12 kHz. Hearing loss measured by auditory brainstem responses exceeded 55 dB from 6 to 32 kHz. The mRNA from the exposed CN was harvested at 14 or 28 days post-exposure and qRT-PCR analysis was performed on 168 genes involved in neural inflammation, neuropathic pain and glutamatergic or GABAergic neurotransmission. Expression levels of mRNA of Slc17a6 and Gabrg3, involved in excitation and inhibition respectively, were significantly increased at 28 days post-exposure, suggesting a possible role in the CN spontaneous hyperactivity associated with tinnitus and hyperacusis. In the pain and inflammatory array, noise exposure up-regulated mRNA expression levels of four pain/inflammatory genes, Tlr2, Oprd1, Kcnq3 and Ntrk1 and decreased mRNA expression levels of two more genes, Ccl12 and Il1β. Pain/inflammatory gene expression changes via Ntrk1 signaling may induce sterile inflammation, neuropathic pain, microglial activation and migration of nerve fibers from the trigeminal nerve and cuneate and vestibular nuclei into the CN. These changes could contribute to somatic tinnitus, hyperacusis and otalgia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Manohar

Dahar

Adler

et al. 2016

Molecular and Cellular Neuroscience

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“…Whether components of the small cell cap or granule cell layers project to central pain pathways remains to be determined. However, recent work has shown that damaging sound increased activity-dependent c-Fos expression in the granule cell region of the cochlear nucleus (39). It also has been suggested that activation of type II afferents drives medial olivocochlear efferents to suppress cochlear sensitivity (40), although that hypothesis is difficult to reconcile with the fact that medial olivocochlear efferents have acoustic tuning and sensitivity similar to those of type I afferents (41).…”

Section: Discussionmentioning

confidence: 99%

Unmyelinated type II afferent neurons report cochlear damage

Liu

Glowatzki

Fuchs

2015

Proc. Natl. Acad. Sci. U.S.A.

114

102

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In the mammalian cochlea, acoustic information is carried to the brain by the predominant (95%) large-diameter, myelinated type I afferents, each of which is postsynaptic to a single inner hair cell. The remaining thin, unmyelinated type II afferents extend hundreds of microns along the cochlear duct to contact many outer hair cells. Despite this extensive arbor, type II afferents are weakly activated by outer hair cell transmitter release and are insensitive to sound. Intriguingly, type II afferents remain intact in damaged regions of the cochlea. Here, we show that type II afferents are activated when outer hair cells are damaged. This response depends on both ionotropic (P2X) and metabotropic (P2Y) purinergic receptors, binding ATP released from nearby supporting cells in response to hair cell damage. Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term "noxacusis" to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber's response to hair cell damage. Type II afferents may be the cochlea's nociceptors, prompting avoidance of further damage to the irreparable inner ear.type II cochlear afferents | ATP | acoustic trauma | hyperacusis | noxacusis T he mammalian cochlea is the most elaborate of vertebrate auditory organs. The elegantly coiled, mechanically tuned cochlear duct and functional differentiation between inner hair cells (IHCs) and outer hair cells (OHCs), afferent and efferent neuronal connections are among the features that enable the widest acoustic frequency range and most complex vocalizations among vertebrate species. This benefit, however, has been gained at a significant cost in the metabolic and mechanical vulnerability of cochlear hair cells and neurons. Loud sound progressively damages type I afferent neurons and OHCs (1). Once damaged beyond repair, these do not regenerate as they do in nonmammalian vertebrates, suggesting that protective mechanisms should exist to preserve cochlear function. Indeed, middle ear reflexes (2) and efferent inhibition of hair cells (3) can mitigate acoustic trauma to some extent. However, a more effective strategy is simply to avoid or withdraw from sources of trauma, by analogy to limb withdrawal triggered by C-fiber activation in skin.Here, we provide evidence that unmyelinated type II cochlear afferents can report cochlear trauma, a potential trigger for nocifensive behavior. Hyperactivity of type II neurons could contribute as well to the paradoxical hypersensitivity to loud sound that can accompany hearing loss, despite diminished type I afferent function. Hyperacusis is a comorbidity in 80% of tinnitus patients (4) suggesting common pathogenic mechanisms (5). In the most severe cases, hyperacusis is described as debilitating "ear pain" (6). The response to trauma by type II afferents may relate most directly to such ...

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“…Despite this extended dendritic arbor, type II afferents are only weakly activated by hair cell glutamate release (Weisz et al 2009;Weisz et al 2012) and are insensitive to sound Robertson 1984;Robertson et al 1999), although they project centrally in parallel with neighboring type I afferents (Berglund and Brown 1994;Brown et al 1988;Brown and Ledwith 1990;Morgan et al 1994). Emerging evidence suggests that type II afferents instead respond to tissue damage (Flores et al 2015;Liu et al 2015) perhaps to serve as cochlear nociceptors. Further insight into type II function will require knowledge of their central connectivity, as well as animal models in which type II function can be altered selectively.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine Hydroxylase Expression in Type II Cochlear Afferents in Mice

Vyas

Zimmerman

et al. 2016

JARO

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Acoustic information propagates from the ear to the brain via spiral ganglion neurons that innervate hair cells in the cochlea. These afferents include unmyelinated type II fibers that constitute 5 % of the total, the majority being myelinated type I neurons. Lack of specific genetic markers of type II afferents in the cochlea has been a roadblock in studying their functional role. Unexpectedly, type II afferents were visualized by reporter proteins induced by tyrosine hydroxylase (TH)-driven Cre recombinase. The present study was designed to determine whether TH-driven Cre recombinase (TH-2A-CreER) provides a selective and reliable tool for identification and genetic manipulation of type II rather than type I cochlear afferents. The BTH-2A-CreER neurons^radiated from the spiral lamina, crossed the tunnel of Corti, turned towards the base of the cochlea, and traveled beneath the rows of outer hair cells. Neither the processes nor the somata of TH-2A-CreER neurons were labeled by antibodies that specifically labeled type I afferents and medial efferents.TH-2A-CreER-positive processes partially co-labeled with antibodies to peripherin, a known marker of type II afferents. Individual TH-2A-CreER neurons gave off short branches contacting 7-25 outer hair cells (OHCs). Only a fraction of TH-2A-CreER boutons were associated with CtBP2-immunopositive ribbons. These results show that TH-2A-CreER provides a selective marker for type II versus type I afferents and can be used to describe the morphology and arborization pattern of type II cochlear afferents in the mouse cochlea.

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A Non-canonical Pathway from Cochlea to Brain Signals Tissue-Damaging Noise

Cited by 124 publications

References 39 publications

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Unmyelinated type II afferent neurons report cochlear damage

Tyrosine Hydroxylase Expression in Type II Cochlear Afferents in Mice

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